Carbamide peroxide compositions for the treatment of dermatological disorders and methods for their use

ABSTRACT

Topical compositions which include urea and carbamide peroxide are described. Compositions having a pH in the acidic range, particularly in the range of about 2.5 to about 9 are also described. Methods for treating dermatological disorders using the composition are also described.

FIELD OF THE INVENTION

This present disclosure relates to compositions containing carbamideperoxide and urea as components for the treatment of dermatologicaldisorders.

BACKGROUND OF THE INVENTION

There is a need to provide carbamide peroxide compositions, which areeasily and economically prepared, which have a smooth textureappropriate for cosmetic products, and which are enhanced by exhibitinggreater keratolytic and antibacterial effects. Compositions havingcarbamide peroxide and urea as components might satisfy such a needbecause urea has keratolytic activity and has the property of denaturingand solubilizing proteins in addition to antimicrobial activity.However, urea containing formulations generally tend to be neutral toslightly alkaline, while carbamide peroxide formulations are generallymost stable under acidic conditions.

SUMMARY

The present invention relates to a topical composition that combines thebenefits of urea and carbamide peroxide and yet achieves a stableformulation. In one embodiment the topical composition comprisescarbamide peroxide, urea, and a dermatologically acceptable carrier,wherein the composition has a pH between about 2.5 and about 9. Inanother embodiment the topical composition comprises about 0.5 to about30% by weight carbamide peroxide, about 0.1 to about 40% urea by weight;and a dermatologically acceptable carrier.

The topical composition of the invention can be useful in treatingdermatological disorders. Examples of dermatological disorders that canbe treated by the composition include disorders due to changes in normalkeratinization, epidermal formation or pilosebaceous function, such asacne, psoriasis, seborrhea, ingrown hairs and pseudofolliculitis barbae,and hyperpigmented skin.

In one embodiment, the invention provides a method for treating adermatological disorder comprising administering to a subject in needthereof a topical composition of the invention.

DETAILED DESCRIPTION OF THE INVENTION

Overview

Carbamide peroxide and urea are pharmacological agents useful for thetreatment of dermatological disorders. However, carbamide peroxide andurea have generally been considered incompatible. Carbamide peroxide canbe extremely unstable. Thus, stability of carbamide peroxide is animportant factor in formulating compositions containing carbamideperoxide. Carbamide peroxide formulations are generally most stableunder acidic conditions. However, urea containing formulations generallytend to be neutral to slightly alkaline.

The novel compositions disclosed herein combine the benefits of urea andcarbamide peroxide and yet achieve a stable formulation. In oneembodiment, such a composition is achieved by use of an optimized buffersystem that maintains the pH of the formulation at an optimal acidicrange.

Topical Composition

The invention provides topical compositions comprising carbamideperoxide and urea. The desired amount of urea and carbamide peroxide canvary from composition to composition depending on the particulardisorder or disorders being treated, the severity of the disorder, theduration of the treatment, the other specific components of thecomposition being used, and like factors. In one embodiment, thecarbamide peroxide can be present in the composition at a concentrationfrom about 0.5% to about 30% by weight and the urea can be present fromabout 0.1% to about 40% by weight, relative to the weight of thecomposition. In another embodiment, the carbamide peroxide can bepresent in the composition at a concentration from about 4 to about 15%by weight. In yet another embodiment, the carbamide peroxide can bepresent in the composition from about 4.5% to about 9% by weight. Instill another embodiment, the urea can be present from about 5% to about20% by weight, relative to the weight of the composition.

In one embodiment, the compositions of the invention are acidic.Carbamide peroxide is generally most stable under acidic conditions,while urea containing formulations generally tend to be neutral toslightly alkaline. As disclosed herein, acidic compositions includingboth carbamide peroxide and urea tend to be more stable under acidicconditions. In addition to allowing formation of a stable composition, apH in an acidic range is also therapeutically useful. Generally,traumatized skin tends to have a higher pH and skin healing is aided bymaintaining a slightly acidic pH. Thus, the novel formulations of thisinvention combine the benefits of urea and carbamide peroxide and yetachieve a stable formulation by the use of an optimized buffer systemwhich maintains the pH of the formulation at an optimal acidic range.According to one embodiment of the invention, the composition has a pHless than 9. In another embodiment, the compositions have a pH in therange of about 2.5 to about 9.

Any dermatologically acceptable carrier can be used in the compositionsof the invention. As used herein, “determatologically acceptablecarrier” refers to vehicles, diluents, carries, which can includeadjuvants, additives, or excipients, known for use in dermatologicalcompositions. The compositions of the invention include, but are notlimited to, creams, ointments, solutions, lacquers, sticks, pledgets,wipes, cleansers and/or gels.

In one embodiment, the topical composition is a semi-solid at roomtemperature but is easily absorbed into the stratum comeum. Thesemi-solid composition can be a cream. Such a composition can includepetroleum-based liquids and solid fractions as skin protectants. Thesolid skin protectant can be semi-solid. The solid skin protectant canbe present in about 1.0% to about 20% in the composition and includespetrolatum or a synthetic or semi-synthetic hydrocarbon of the samenature as petrolatum. Mixtures of such ingredients can also be used.Liquid skin protectants can be petrolatum and contained in thecomposition in about 1.0% to about 20% and include any synthetic orsemi-synthetic oleaginous liquid fraction. The liquid skin protectantcan be mineral oil, which is a liquid mixture of hydrocarbons obtainedfrom petroleum.

The compositions of the invention can include propylene glycol.Propylene glycol can be present in the composition up to about 5%. Inone embodiment, propylene glycol is present in the composition at about1% to about 5%.

The compositions can contain conventional preservatives, such as methylparaben, propyl and butyl imidazolidinylurea, diazolidinylurea,methylchloroiso-thiazolinone and methylisothiazolinone. Although not tobe held by theory, it is believed that the antibacterial properties ofthe urea and carbamide peroxide and propylene glycol allow thecomposition of the present invention to be free of conventionalpreservatives.

The present compositions can also contain dermatologically acceptableexcipients, such as for example emulsifiers and thickeners. Among theseare for example C₁₆ to C₁₈ straight or branched chain fatty alcohols orfatty acids or mixtures thereof. Examples of emulsifiers and thickenersinclude cetyl alcohol, stearyl alcohol, stearic acid, palmitic acid, normixtures thereof. Fatty acids or fatty alcohols may be present in fromabout 0.25 to 2 wt-%.

Another ingredient useful in the composition of the present inventionmay be glyceryl stearate, which is a monoester of glycerine and stearicacid, or other suitable forms of glyceryl stearate for example glycerylstearate SE, which is a commercially available self-emulsifying grade ofglycerol stearate that contains some sodium and/or potassium stearate.Glyceryl stearate may be in the composition anywhere from about 1 toabout 3% by weight.

Xanthan gum is another ingredient which may be used in the presentcompositions. Xanthan gum is a high molecular weightheteropolysaccharide gum produced by pure-culture fermentation of acarbohydrate with Xanthomonas campestris. The gum is also commerciallyavailable from various sources.

The composition can be an emulsion including liposomes. The emulsion cancontain a fatty phase in the range of about 5% to about 80% by weight.Typically, the fatty phase will range from about 5% to about 50% byweight, with respect to the total weight of the composition. Known oils,waxes, emulsifiers and coemulsifiers can be used in compositions in theemulsion form. The emulsifier and the coemulsifier can be present, inthe composition, in a proportion ranging from about 0.3% to about 30% byweight. Typically the emulsifier and the coemulsifier are present in aproportion ranging from about 0.5 to about 20% by weight. The emulsioncan also contain lipid vesicles.

In one embodiment, the composition can include thickeners which providea high viscosity cream designed to remain in place upon application tothe skin. By way of example, thickeners can include a mixture of acarbomer and triethanolamine. The mixture can be combined together andadded to the composition in an amount totaling anywhere from about 0.05to 30% by weight. Triethanolamine can be purchased as Trolamine NF fromBASF. Carbomers come in various molecular weights and are identified bynumbers. These are otherwise known as Carbopol. Exemplary Carbopolsinclude is Carbopol 940, 910, 2984, 5984, 954, 980, 981, 941 and 934.Carbopol ETD 2001, 2020, and 2050 and Ultrez 20 are also commerciallyavailable and can be used. The carbomer or Carbopols are resins whichare known thickening agents. They are homopolymers of acrylic acidcrosslinked with an allyl ether of pentaerythritol, an allyl ether ofsucrose or an allyl ether of propylene. The carbomer can be present inthe composition as a thickener and also can be used to suspend andstabilize the emulsion.

The composition can also contain known adjuvants and additives, such asbactericides, fungicides, virucides, light filter substances, activeingredients with a cooling action, antioxidants, plant extracts,anti-inflammatories, substances which promote wound healing,skin-lightening agents, screening agents, odor absorbers, skin-coloringagents, perfumes, antifoams, dyes, pigments which have a coloringaction, thickeners, surface-active substances, emulsifiers, emollients,moisturizers and/or humectants, fats, oils, waxes, alcohols, polyols,polymers, foam stabilizers, electrolytes, organic solvents, siliconederivatives or chelating agents. These additives and adjuvants,depending on their nature, can be introduced into the fatty phase, intothe aqueous phase and/or into the lipid spherules.

Exemplary oils or waxes suitable for use in the compositions includemineral oils (liquid petrolatum), vegetable oils (liquid fraction ofkarite butter, sunflower oil), animal oils (perhydrosqualene), syntheticoils (purcellin oil), silicone oils or waxes (cyclomethicone) andfluorinated oils (perfluoropolyethers), beeswax, camauba wax or paraffinwax. Fatty alcohols and fatty acids (stearic acid) can be added to theseoils.

Exemplary emulsifiers which are suitable include glyceryl stearate,polysorbate 60 and the PEG-6/PEG-32/glycol stearate mixture marketedunder the trademark Tefose.RTM. 63 by Gattefosse.

Exemplary solvents which can be used in the compositions include thelower alcohols, such as ethanol, isopropanol, acetone and propyleneglycol.

Exemplary hydrophilic gelling agents suitable for use in thecompositions include carboxyvinyl polymers (carbomer), acryliccopolymers such as acrylate/alkyl acrylate copolymers, polyacrylamides,polysaccharides such as hydroxypropylcellulose, natural gums and clays.And exemplary lipophilic gelling agents include modified clays such asbentones, metal salts of fatty acids such as aluminum stearates, andhydrophobic silica, ethylcellulose or polyethylene.

The compositions can contain other hydrophilic active principles, suchas proteins or protein hydrolysates, amino acids, polyols, urea,allantoin, sugars and sugar derivatives, water-soluble vitamins, plantextracts, e.g. aloe and hydroxy acids.

Representative lipophilic active principles include retinol (vitamin A)and derivatives thereof, tocopherol (vitamin E) and derivatives thereof,essential fatty acids, ceramides, essential oils or salicylic acid andderivatives thereof.

Suitable antioxidants that can be used in the compositions includetocopherols (vitamin E), tocopherol derivatives, tocotrienols, ascorbicacid (vitamin C), ascorbic acid derivatives, carotenoids, vitamin A orderivatives thereof, butylated hydroxytoluene, butylated hydroxyanisole,gallic esters, flavonoids such as, for example, quercetin or myricetin,catechins such as, for example, epicatechin, epicatechingallate,epigallocatechin or epigallocatechingallate, sulfur-containing moleculessuch as, for example, glutathione, cysteine, lipoic acid,N-acetylcysteine, chelating agents such as, for example, ethylenediaminetetraacetic acid or other customary antioxidants. Antioxidants can beincluded in the compositions at about 0.0001 to about 30% by weight.Typically antioxidants will be included from about 0.0001 to about 20%by weight. Most often antioxidants will be included from about 0.0001 toabout 5% by weight, based on the total weight of the preparation.

Additional antibiotic agents can be included in the compositions of theinvention. Preferably the antibiotics are dermatologically absorbable.Suitable dermatologically absorbable antimicrobial, antibiotic,antibacterial or antifungal agents include erythromycin, bacitracin,zinc bacitracin, polymycin, neomycin, chloramphenicol, tetracycline,minocycline, clindamycin, doxycycline, undecylenic acid and saltsthereof, propionic acid and salts thereof, caprylic acid and saltsthereof, ciprofloxacin, cephlasporins, benzoic acid, ciclopiroxolamine,clotrimazole, econazole nitrate, metronizadole, miconazole nitrate,ketacanazole, oxiconazole, tolnaftate.

Antifungal agents can also be included in the compositions of theinvention. These include, for example, amoroline, betadine, bifonazole,clotrimazole, econazole nitrate, isoconazole, ketoconazole, miconazolenitrate, naftifine hydrochloride, oxiconazole, sulfanazole, terbinafine,ticonazole, tolnaftate, and undecenoates.

Additional keratolytic agents such as salicylic acid and alpha hydroxyacids can be included in the composition.

Dermatological Disorders

The invention provides a method for treating a dermatological disordercomprising administering to a subject in need thereof a topicalcomposition of the invention. As used herein, “treating” or “treatment”means the prevention or reduction of severity of symptoms or effect of adermatological disorder. A “subject” according to the invention refersto any multicellular organism having skin. Typically, the subject willbe a mammal, such as a mouse, a rat, a pig, a horse, a cat, a dog, anelephant, a giraffe, a monkey, or a human, and the like. Typically, themammal will be a human.

The term “administering” as used herein refers to any method which, insound medical practice, delivers the composition to a subject in such amanner to so as to be effective in the treatment of a dermatologicaldisorder. The compositions are preferably administered such that theycover the entire area to be treated.

The phrase “safe and effective amount”, as used herein, means an amountof a composition or component thereof sufficient enough to positivelymodify the disorder to be treated but low enough to avoid serious sideeffects, within the scope of sound medical advice. Safe and effectiveamounts will vary with the particular disorder or disorders beingtreated, the severity of the disorder, the duration of the treatment,the specific components of the composition being used, and like factorsas are known by health-care providers, including physicians.

As used herein, “dermatological disorder” refers to any disorder ofskin, hair, or glands. A dermatological disorder can be manifest in theform of visible lesions, pre-emergent lesions, pain, sensitivity totouch, irritation, inflammation, or the like. Dermatological disordersinclude disorders of the cutaneous and pilosebaceous unit or the processof keratogenesis. For example, a dermatological disorder can be adisorder of the epidermis or dermis, or within and surrounding thepilosebaceous follicle, which is located within the skin's epidermis,dermis, or both. Examples of dermatological disorders include acne,psoriasis, seborrhea, ingrown hairs and pseudofolliculitis barbae, andhyperpigmented skin, cutaneous infections, and the like.

The invention provides a composition comprising carbamide peroxide andurea. Accordingly, the compositions can be useful for treatingdermatological disorders for which carbamide peroxide or urea are knownto be useful. Urea has been long recognized as a cosmetic ingredient informulations acting as a humectant and moisturizer. Urea also haskeratolytic activity and has the property of denaturing and solubilizingproteins. Additionally, it has been found that urea has mildantimicrobial activity. Carbamide peroxide has been employed as akeratolytic drug and as an antibacterial agent in the past, but ismostly used in to soften earwax. The combination of urea and carbamideperoxide provides synergistic antimicrobial activity. Keratolytic agentsare agents that can remove or sluff dead cells of the horny outer layerof the skin (stratus corneum), which are composed largely of keratin.Such agents can prevent obstruction of follicular ducts or reopenobstructed ducts. Thus, the compositions can be useful for treatingdermatological disorders in which a humectant, moisturizer, keratolyticagent, antibacterial agent, protein denaturant or solubilizer, or acombination thereof would be beneficial. Such disorders include anydisorder involving obstruction of a follicular duct or bacterialinfection. In addition, carbamide peroxide has been useful, and thus thecompositions of the invention would be useful, in the topical treatmentof skin lesions such as acne, burns, varicose ulcers, sycosis vulgaris,seborrhea and rosacea.

The compositions of the invention can also be used to treatdermatological disorders resulting in visible lesions. Examples of suchdisorders include acne, cutaneous infections, psoriasis and otherdisorders of the cutaneous and pilosebaceous unit or the process ofkeratogenesis. Visible lesions include closed comedones, open comedones,red or pustular-looking inflamed papules, pustules, nodules and cysts ofacne or cutaneous infection; visible ingrown hairs of pseudofolliculitisbarbae; visible scales of seborrhea, ichthyosis and psoriasis; and thelike. Visible lesions can be due to obstruction of follicular ducts,thickened sebum, bacterial infection, or a combination thereof.Accordingly, the compositions can be used to prevent obstruction offollicular ducts, to reopen a duct if it has become blocked, to combatthickened sebum, to combat bacterial infection, or a combination thereofTreatment of visible lesions can be evaluated based on the effectivenessof the treatment in reducing the number and severity of visible lesions.Any reduction in number or severity of visible lesions as a result ofadministration a composition would be considered treatment of visiblelesions.

In one embodiment, the compositions of the invention can be used totreat pre-emergent lesions. As used herein, “pre-emergent lesions”refers to non-visible lesions present within the skin prior to eruptionof visible lesions on the surface of the skin. Like visible lesions,pre-emergent lesions can be due to obstruction of follicular ducts,thickened sebum, bacterial infection, or a combination thereof.Accordingly, the compositions can be used to treat pre-emergent lesionsby preventing obstruction of follicular ducts, reopening a duct if ithas become blocked, combating thickened sebum, combating bacterialinfection, or a combination thereof While pre-emergent lesions areinsufficiently visible to be graded in conventional clinical studies,their presence within the skin can be discerned by the tactile sense offeel and/or by pain and tension within the skin. Any reduction in numberof locations within the skin in which pre-emergent lesions exist as aresult of administration of a composition would be considered treatmentof pre-emergent lesions. Similarly, any reduction in the severity of thesymptoms of a pre-emergent lesion as a result of administration of acomposition would be considered treatment of the pre-emergent lesion.

In another embodiment, the compositions of the invention can be used totreat acne. As used herein, “acne” means a disorder of the skin causedby inflammation of skin glands or hair follicles. The compositions ofthe invention can be used to treat acne at early pre-emergent stages orlater stages where lesions from acne are visible. Early pre-emergentstages of acne usually begins with an excessive secretion of sebum ordermal oil from the sebaceous glands located in the pilosebaceousapparatus. Sebum reaches the skin surface through the duct of the hairfollicle. The presence of excessive amounts of sebum in the duct and onthe skin tends to obstruct or stagnate the normal flow of sebum from thefollicular duct, thus producing a thickening and solidification of thesebum to create a solid plug known as a comedone. In the normal sequenceof developing acne, hyperkeratinazation of the follicular opening isstimulated, thus completing blocking of the duct. The usual results arepapules, pustules, or cysts, often contaminated with bacteria, whichcause secondary infections. Acne is characterized particularly by thepresence of comedones, inflammatory papules, or cysts. The appearance ofacne may range from slight skin irritation to pitting and even thedevelopment of disfiguring scars. Accordingly, the compositions of theinvention can be used, but not limited, to treat skin irritation,pitting, development of scars, comedones, inflammatory papules, cysts,hyperkeratinazation, and thickening and hardening of sebum associatedwith acne.

All patent and literature references cited in the present specificationare hereby incorporated by reference in their entirety. All parts andpercentages are by weight unless otherwise specified. All scientific andtechnical terms used in this application have meanings commonly used inthe art unless otherwise specified.

EXAMPLES

The following examples are offered for illustrative purposes only, andare not intended to limit the scope of the present invention in any way.

Example 1 Preparation of Formula I, an Exemplary Composition

Formula I is composed of the ingredients shown in Table 1 and isprepared using the following protocol.

TABLE 1 Component Weight Percent A. Hydrous Carbamide Peroxide (milled)15.0%  Propylene Glycol 3.0% Purified Water 8.0% B. PEG 75 5.0% GlycerylStearate 5.0% Cetyl Alcohol 5.0% White Petroleum 5.0% Polysorbate 602.0% Sorbitan Mono Stearate 1.0% C. Purified Water 36.0%  Citric Acid2.0% Urea 10.0%  Xanthan Guan 0.5% Aloe Vera Aqueous Extract Concentrate1.0% D. Sodium Hydroxide (10% Solution) to pH 4-8.) E. Purified Water QS(quantity sufficient) 100.0% 

Method

1. In the main mixing tank place components of B. and heat to 75° C. andmix.

2. Separately dissolve Citric Acid and Urea in Purified Water (C) anddisperse Xanthan Gum and Aloe Concentrate. Let stand.

3. From Step 2 heat to about 75° C. into main tank while mixing.Homogenize then cool.

4. Separately combine (A) components carefully and warm to 50-55° C. andadd to main tank when it has cooled to 50-55° C. and continue to mix.

5. Add D to main tank to adjust pH to 4.0-6.0.

6. Add Purified Water to QS the batch.

Example 2 Preparation of Formula II, an Exemplary Composition

Formula II is composed of the ingredients shown in Table 2 and isprepared using the following protocol.

TABLE 2 Component Weight Percent A. Hydrous Carbamide Peroxide (milled)15.0% Propylene Glycol  5.0% Glycerine 10.0% Purified Water 10.0% B.Triethanolamine  1.50% Purified Water 10.0% C. Purified Water 10.0%Carbomer 940  1.5% Citric Acid  2.0% Urea 10.0% D. Aloe Vera AqueousExtract Concentrate  1.0% E. Purified Water QS 100.0% 

Method

1. Place components of C in the main mixing tank as follows. To thePurified Water add urea, citric acid and mix to dissolve. Then dispersethe Carbomer 940 and mix. Let stand.

2. Separately, (carefully) combine the components A in a mixing tank,mill to smooth consistency and mix.

3. While mixing add A (Step 2) to the main tank.

4. Separately combine components of B and add to the main tank. Continueto mix carefuilly.

5. Add Aloe concentrate to the batch and continue to mix

6. Add Purified Water (D) to QS the batch.

Although the present invention has been described in terms of specificembodiments, changes and modifications can be carried out withoutdeparting from the scope of the invention which is intended to belimited only by the scope of the appended claims.

We claim:
 1. A method for treating a dermatological disorder comprisingadministering to a subject in need thereof a topical compositioncomprising: (a) about 0.5 to about 30 weight % carbamide peroxide; (b)about 0.1 to about 40 weight % urea; and (c) a dermatologicallyacceptable carrier, wherein the dermatological disorder is selected fromthe group consisting of acne, psoriasis, seborrhea, ingrown hairs,pseudofolliculitis barbae, hyperpigmented skin, and cutaneous infection.2. The method of claim 1, wherein the dermatological disorder is acne.